The overall goal of this Mentored Research Scientist Development Award (K01) Application is to become an expert in applying translational methods to study the etiology of substance use, by identifying specific genetic and neurobiological pathways that mediate individual risk to substance use and its related behavioral disorders. Exposure to prenatal smoking provides an excellent model with which to obtain these skills, while simultaneously tackling a serious public health problem. Despite the overall declining trends, smoking during pregnancy remains a leading cause of preventable illness among both mothers and offspring. Offspring of mothers who smoke during pregnancy are at heightened risk for a range of neonatal, as well as long-term behavioral and substance use disorders. Even though mothers who smoke while pregnant are likely to continue smoking during other times in the child's life, at least some of the above associations appear specific to prenatal exposure, suggesting an underlying biological mechanism. In the proposed study, I will examine the roles that genes and brain circuitry play in mediating the relationships between prenatal exposures and offspring behavioral and substance use disorders. The study will build upon a longitudinal three-generation cohort that has been prospectively followed for up to 25 years on a range of diagnostic measures, and now further includes genetic (DNA) markers and MRI scans. I will implement an additional assessment schedule that follows the cohort prospectively on new diagnostic as well as behavioral measures related to smoking, drug and alcohol use. I will first examine the association between prenatal exposure and the above outcome measures, while controlling for potential confounds, and examine the progression from behavioral problems to substance use disorders (Aim 1). I will then test the hypothesis that functionally altering variations within the monoamine oxidase A gene (as well as other genes of interest, particularly within the nicotinic and dopaminergic families) moderate the risk to offspring conferred by exposure to maternal smoking (Aim 2). Using an fMRI task that indexes response inhibition (the Simon Spatial Incompatibility Task), I will next assess whether disruptions to behavioral circuits involved in self-regulatory behaviors mediate the association between prenatal smoking and offspring psychopathology (Aim 3). Finally, I will integrate the genetic and neuroimaging data to explore whether genotype moderates the association between prenatal exposure and cortical circuitry, and explore how genes, exposures, and cortical circuitry interact on the pathway to risk (Aim 4). Even though I bring to this application strength in psychiatric and imaging research, I need to (1) develop further expertise in the epidemiology, etiology, and assessment of substance use and its related syndromes. This will thus form a backbone of my 5-year training plan. In addition, I will seek training in (2) genetics, including methods of genetic analysis and the integration of imaging and genetic data, as well as (3) further methodological expertise in the use of longitudinal epidemiological and healthcare data to address trajectories of smoking and substance use. Finally, I will continue to receive training in the ethical conduct of research. To achieve these goals, I am fortunate to have Myrna M. Weissman, Ph.D., the Chief of the Division of Epidemiology, as my primary mentor, supported by Frances R. Levin, M.D., Deborah S. Hasin, Ph.D. as co- mentors for training in substance use, and Steven P. Hamilton, M.D., Ph.D., for additional training in genetics. Few studies have examined the role of genes in moderating outcomes of prenatal exposures, and none with further indices of brain function. If funded, this study would be the first to directly test the role of genetic variation and brain circuitry in the context of risks conferred by prenatal exposures. The execution of the research plan, in conjunction with the training aims, will enable me (1) learn about and test biological pathways mediating behavioral disorders; (2) to identify offspring groups who may be at greatest risk for these disorders and may require earlier or more targeted intervention; and ultimately (3) to export these skills to study other exposures, genetic pathways, and behavioral outcomes relevant to addictive disorders. The study will be conducted at New York State Psychiatric Institute and Columbia University Department of Psychiatry, which together form an active academic medical center and leading teaching hospital, and include a distinguished group of research scientists devoted to the study of psychiatric and substance use disorders. Should this award be funded, I will commit to devoting at least 75% of my full time effort on this project, and the institution has guaranteed to provide me the freedom to do so.